Abscopal effect of stereotactic radiotherapy combined with anti-PD-1/PD-L1 immunotherapy: Mechanisms, clinical efficacy, and issues

Immunotherapy, as one of the major strategies for cancer treatment, has shown promising efficacy in cancer treatment by the clinical application of programmed cell death protein-1/ programmed cell death-ligand 1 (PD-1/PD-L1) antibodies which have demonstrated a significant prolongation in the survival time of melanoma, lung, and liver cancer patients. [1-3]. Meanwhile, the clinical observation of partial responses in unirradiated lesions after radiotherapy, termed as abscopal effect, has gradually attracted a lot of attention and has inspired oncologists to combine stereotactic radiotherapy (SABR) with immunotherapy for improving clinical outcomes. It is the abscopal effect phenomenon that crucially determines the anti-tumor efficiency of SABR and immune checkpoint inhibitors combination strategy [4]. However, due to the short application time and limited experience of the clinical utilization of SABR and anti-PD-1/PD-L1 combination therapy, there are plenty of theoretical and practical issues that need to be systematically discussed, including the mechanisms underlying an abscopal effect, the efficacy and toxicity of combination therapy, and the validity or reliability of corresponding clinical trials. Here, we reviewed previous landmark reports and summarized the research progress of SABR combined with anti-PD-1/PLD-1 therapy to improve the understanding on abscopal effect.

1 THE POSTULATED MECHANISM OF THE ABSCOPAL EFFECT IN SABR AND ANTI-PD1/PD-L1 COMBINATION THERAPY

The abscopal effect phenomenon in SABR and anti-PD1/PD-L1 combination therapy involves a series of chain reactions. First, high-dose of ablative radiation induces DNA double-strand breaks and damages the tumor cells. Second, the damaged cells release large amounts of tumor-associated antigen (TAA) fragments into the blood within a short time for antigen-presenting cells, called antigen outbreak. During this process, cascades of inflammatory cytokines, such as interleukins (IL) and tumor necrosis factors (TNFs), are secreted simultaneously, Subsequently, these TAA fragments and inflammatory cytokines are recognized and engulfed by dendritic cells, which thereby promotes the dendritic cells’ cross-presenting tumor antigens on class I major histocompatibility complex (MHC) for activating cytotoxic T cells. Finally, the activated polyclonal antigen-specific T cells are recruited to attack the tumor cells outside the irradiated field deliberately. In particular, those cascade immune reactions originated by TAA fragments approve the participation of other immune checkpoint inhibitors [5-9]. Therefore, anti-PD1/PLD-1 antibodies could theoretically enhance the anti-tumor immune modulation of SABR and achieve better outcomes synergistically [9-11]. The process of the abscopal effect described above elucidated that based on the antigen outbreak microenvironment triggered by SABR, the immune modulation, which acts as a bridge, could be dramatically elevated via the co-stimulation of anti-PD1/PD-L1 antibodies, and thus exert an obvious killing effect on tumors (Figure 1).

2 CLINICAL EFFICACY OF THE ABSCOPAL EFFECT IN SABR AND ANTI-PD1/PD-L1 COMBINATION THERAPY

Early observations on the abscopal effect were reported by some independent clinical cases, which subsequently encourages the progress of systematic investigations in this field. With the advancement in radiobiology at different periods, various new biological theories have been proposed by oncologists to reasonably explain and support the abscopal effect. However, the effectiveness and efficiency of the abscopal effect, as well as the radiobiological mechanism, remain unclear until now. In 2012, Postow et al. [11] published a landmark case on the abscopal effect in the New England Journal of Medicine and was the first report about those specific manifestations after immunotherapy. This case, together with the related phenomenon, caused wide public concern and a growing number of similar reports have been since published in various journals. Several studies [12-19] have detailed the characteristics and results of clinical cases after SABR and anti-PD-1/PD-L1 combination treatment over the recent years (Table 1). However, public opinions are still polarized on those insufficient statistical results regarding the abscopal effect. On one hand, the incidence of the abscopal effect is relatively low. On the other hand, there is no uniform standard for evaluating the occurrence and level of the abscopal effect to date. Some studies, therefore, raised the controversial question of whether the regression of unirradiated abscopal tumors should attribute to the context of SABR and immune checkpoint combination therapy or the latter alone. Based on the thorough review of the previous findings and reports, we summarize the clinical key points of the abscopal effect as follows: 1) the phenomenon of the abscopal effect does exist. 2) the exact identification and evaluated-criteria for the abscopal effect are urgently needed via high-level evidence-based medical researches. 3) the overall incidence of the abscopal effect in the clinic is relatively low; 4) no prospective studies with large sample sizes and long follow-up periods in this field have been conducted till now, and 5) classifying the targeted beneficiary group will be the further step in the abscopal effect exploration [20]. These suggest that the clinical efficacy of the abscopal effect in the context of radiation and immune checkpoint combination therapy needs to be firmly confirmed in future investigations (Table 1). More importantly, extensive investigations are required before taking the advantage of the abscopal effect in conducting the clinical treatment (Table 2).

3 ISSUES TO BE SOLVED FOR THE ABSCOPAL EFFECT OF SABR AND ANTI-PD-1/PLD-1 COMBINATION THERAPY

3.1 What are the underlying molecular mechanisms of the abscopal effect?

The phenomenon of spontaneous regression in unirradiated tumors is defined as the abscopal effect, which is commonly found after SABR, and hypothetically attributed to an increase in immune response evoked by tumor antigens cascade. However, it is very difficult to identify the presence and strength of the abscopal effect in clinical reality due to the unmeasurable activation of the immune response. Moreover, some concerns are raised that the shrink of abscopal tumors may entirely be induced by immunotherapy but not SABR, especially in patients who received SABR and immune-checkpoint inhibitors at the same time. However, we speculate that the partial or complete regression of unirradiated tumors after SABR combined with immunotherapy, particularly in the patients with stable or progressive conditions after immunotherapy alone, should be ascribed to the occurrence of the abscopal effect (Figure 2). Accordingly, comparing the response rate of abscopal tumors in the homogeneous metastasis group who received immunotherapy alone or SABR combined immunotherapy separately, could be an appropriate strategy in conducting related clinical trials [21]. Indeed, owing to the various efficacy of each independent case, a clear distinction between the abscopal effect and immune-checkpoint inhibiting effect is also practically needed.

Besides, not only imaging examinations but also advanced technology should be used to qualify and quantify the abscopal effect such as AI, radiomics, and radio-genomics techniques. Meanwhile, biomarkers of abscopal effect such as antigen outbreak fragments, tumor-related molecules, and circulating immune factors, also need to be further researched and validated.

4 CONCLUSION

The abscopal effect is an important mechanism of stereotactic ablative radiotherapy (SABR) combined with immunotherapy on killing tumor cells. SABR kills tumor cells to release tumor-associated antigens and activates immune responses in the human body. However, SBAR combined with PD-1/PD-L1 inhibitor has only been applied in clinical practice for a short time, and most findings are from clinical trials. The abscopal effects are currently far from clear, and the related mechanisms, efficacies, and issues need to be solved in more elaborated studies.

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